Tamm-horsfall protein regulates granulopoiesis and systemic neutrophil homeostasis

Radmila Micanovic, Brahmananda R. Chitteti, Pierre Dagher, Edward Srour, Shehnaz Khan, Takashi Hato, Allison Lyle, Yan Tong, Xue Ru Wu, Tarek Ashkar (El-Achkar)

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Tamm-Horsfall protein (THP) is a glycoprotein uniquely expressed in the kidney. We recently showed an important role for THP in mediating tubular cross-talk in the outer medulla and in suppressing neutrophil infiltration after kidney injury. However, it remains unclear whether THP has a broader role in neutrophil homeostasis. In this study, we show that THP deficiency in mice increases the number of neutrophils, not only in the kidney but also in the circulation and in the liver, through enhanced granulopoiesis in the bone marrow. Using multiplex ELISA, we identified IL-17 as a key granulopoietic cytokine specifically upregulated in the kidneys but not in the liver of THP-/- mice. Indeed, neutralization of IL-17 in THP-/-mice completely reversed the systemic neutrophilia. Furthermore, IL-23 was also elevated in THP-/-kidneys. We performed real-time PCR on laser microdissected tubular segments and FACS-sorted renal immune cells and identified the S3 proximal segments, but not renal macrophages, as a major source of increased IL-23 synthesis. In conclusion, we show that THP deficiency stimulates proximal epithelial activation of the IL-23/IL-17 axis and systemic neutrophilia. Our findings provide evidence that the kidney epithelium in the outer medulla can regulate granulopoiesis. When this novel function is added to its known role in erythropoiesis, the kidney emerges as an important regulator of the hematopoietic system.

Original languageEnglish
Pages (from-to)2172-2182
Number of pages11
JournalJournal of the American Society of Nephrology
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2015

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Uromodulin
Neutrophils
Homeostasis
Kidney
Interleukin-23
Interleukin-17
Protein Deficiency
Liver Circulation
Hematopoietic System
Neutrophil Infiltration
Erythropoiesis
Real-Time Polymerase Chain Reaction
Glycoproteins
Lasers
Epithelium
Bone Marrow
Enzyme-Linked Immunosorbent Assay
Macrophages
Cytokines

ASJC Scopus subject areas

  • Nephrology

Cite this

Tamm-horsfall protein regulates granulopoiesis and systemic neutrophil homeostasis. / Micanovic, Radmila; Chitteti, Brahmananda R.; Dagher, Pierre; Srour, Edward; Khan, Shehnaz; Hato, Takashi; Lyle, Allison; Tong, Yan; Wu, Xue Ru; Ashkar (El-Achkar), Tarek.

In: Journal of the American Society of Nephrology, Vol. 26, No. 9, 01.09.2015, p. 2172-2182.

Research output: Contribution to journalArticle

Micanovic, Radmila ; Chitteti, Brahmananda R. ; Dagher, Pierre ; Srour, Edward ; Khan, Shehnaz ; Hato, Takashi ; Lyle, Allison ; Tong, Yan ; Wu, Xue Ru ; Ashkar (El-Achkar), Tarek. / Tamm-horsfall protein regulates granulopoiesis and systemic neutrophil homeostasis. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 9. pp. 2172-2182.
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